Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.
Wang H., Noordam R., Cade BE., Schwander K., Winkler TW., Lee J., Sung YJ., Bentley AR., Manning AK., Aschard H., Kilpeläinen TO., Ilkov M., Brown MR., Horimoto AR., Richard M., Bartz TM., Vojinovic D., Lim E., Nierenberg JL., Liu Y., Chitrala K., Rankinen T., Musani SK., Franceschini N., Rauramaa R., Alver M., Zee PC., Harris SE., van der Most PJ., Nolte IM., Munroe PB., Palmer ND., Kühnel B., Weiss S., Wen W., Hall KA., Lyytikäinen L-P., O'Connell J., Eiriksdottir G., Launer LJ., de Vries PS., Arking DE., Chen H., Boerwinkle E., Krieger JE., Schreiner PJ., Sidney S., Shikany JM., Rice K., Chen Y-DI., Gharib SA., Bis JC., Luik AI., Ikram MA., Uitterlinden AG., Amin N., Xu H., Levy D., He J., Lohman KK., Zonderman AB., Rice TK., Sims M., Wilson G., Sofer T., Rich SS., Palmas W., Yao J., Guo X., Rotter JI., Biermasz NR., Mook-Kanamori DO., Martin LW., Barac A., Wallace RB., Gottlieb DJ., Komulainen P., Heikkinen S., Mägi R., Milani L., Metspalu A., Starr JM., Milaneschi Y., Waken RJ., Gao C., Waldenberger M., Peters A., Strauch K., Meitinger T., Roenneberg T., Völker U., Dörr M., Shu X-O., Mukherjee S., Hillman DR., Kähönen M., Wagenknecht LE., Gieger C., Grabe HJ., Zheng W., Palmer LJ., Lehtimäki T., Gudnason V., Morrison AC., Pereira AC., Fornage M., Psaty BM., van Duijn CM., Liu C-T., Kelly TN., Evans MK., Bouchard C., Fox ER., Kooperberg C., Zhu X., Lakka TA., Esko T., North KE., Deary IJ., Snieder H., Penninx BWJH., Gauderman WJ., Rao DC., Redline S., van Heemst D.
Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint < 5 × 10-8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint < 5 × 10-8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 2 × 10-6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint < 10-3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.